The liver has a unique ability to grow and regenerate. Liver regeneration is mediated largely by Hepatocyte Growth Factor (HGF) and other growth factors, which act through specific receptor tyrosine kinases (RTKs). However, liver regeneration is impaired in fatty liver disease. During the previous grant cycle we found that cell proliferation in the liver depends on increases in Ca2-i- in the nucleus rather than in cytosol, that changes in nuclear Ca2+ in hepatocytes are mediated by inositol 1,4,5-trisphosphate (lnsP3), and that the RTKs that mediate growth translocate from the cell membrane to the nucleus to locally form lnsP3 and increase Ca2+. While it is established that fatty liver induces endoplasmic reticulum (ER) stress, our preliminary data suggest that fatty liver also induces markers of ER stress within the nuclear envelope and the nucleoplasmic reticulum (NR). A causal link between fatty liver, ER/NR stress, and altered Ca2+ signaling in the nucleus may provide a novel mechanism by which fatty liver disease impairs liver regeneration. Because as many as a third of adults in the US may have NAFLD, this balance between hepatic growth and metabolism is an important clinical problem. We hypothesize that RTKs regulate growth in the liver by inducing lnsP3-mediated Ca2+ signals within the nucleus, but this pathway is impaired by the metabolic changes associated with NAFLD. We will use the HGF receptor c-Met as a model RTK to test this through the following specific aims: (1) The mechanism by which c-Met moves from the plasma membrane to the interior of the nucleus will be determined; (2) The mechanism by which intranuclear c-Met locally generates lnsP3 and thus nuclear Ca2+ signals will be identified; and (3) The effects of NAFLD and induction of ER/NR stress on nuclear Ca2+ signaling pathways and liver growth and regeneration will be examined. These studies will reveal how growth factors and their corresponding RTKs control nuclear Ca2+, and identify whether and how this is impaired in fatty liver, which in turn may give new insights as to why liver regeneration is impaired in NAFLD. Together with Projects 2 and 3, this project should provide an integrated understanding of how nuclear Ca2+ signaling pathways regulate the balance between growth and metabolism in the liver.